Methamphetamine (METH) is a psychostimulant causing prolonged depletion of the neurotransmitter dopamine and dopamine transporter protein in brain. Decreases in dopamine and dopamine transporter protein may cause psychomotor slowing and memory impairments. Methylenedioxymethamphetamine (MDMA, ecstasy) is an amphetamine-derived drug that possesses stimulant and hallucinogenic properties. Although, MDMA is structurally similar to METH, MDMAs effects differ. MDMA affects multiple neurotransmitter pathways, including serotonin, dopamine and norepinephrine. Studies have demonstrated long-term impairments of memory and learning in human subjects reporting heavy MDMA use. Multidrug resistance protein 1a (MDR1a) is a protein located in the blood-brain barrier (BBB) that can transport specific toxic substances in the brain back across the BBB, thereby protecting brain cells from damage. We hypothesize that MDR1a transport of METH and MDMA plays a role in the drugs neurotoxicity. This project uses mdr1a knock-out and wild-type mice to determine 1) whether transport of METH and MDMA by MDR1a results in altered brain concentrations of METH or MDMA and 2) whether these altered brain concentrations correlate with neurotoxicity following METH or MDMA administration. Gas chromatography-mass spectrometry will be used to measure concentrations of METH, MDMA and metabolites in brain and plasma of mdr1a knock-out and wild-type mice following administration of METH or MDMA. High-performance liquid chromatography will be used to measure neurotransmitter concentrations in brains of mdr1a knock-out and wild-type mice after administration of METH or MDMA. Furthermore, levels of neurotransmitter transport proteins in brain also will be measured via Western blotting.